Malfunctions in the dopaminergic system are implicated in a variety of prevalent and debilitating pathologies, e.g. attention deficit disorders, Parkinson's, addiction, and schizophrenia. This project's long-term goal is the development of a positron emission tomography (PET) method that may be applied to better understand dopaminergic neuromodulation at the systems level in the human brain. Such studies would seek to correlate alterations in measures of extracellular dopamine and brain activity in response to stimuli, tasks, or drugs. Because of variation within an individual between scans, it is valuable to simultaneously image dopamine release and changes in regional cerebral blood flow (rCBF). Therefore, this dual tracer method involves a novel protocol for delivering a short lived blood flow tracer, [17F]fluoromethane (t1/2 = 65 s), in the presence of a long lived neurochemical tracer, [11C]raclopride (t1/2 = 20 min). Human studies using this technique would shed light on normal function and mechanisms of disease, and the technique could have diagnostic applications. This project consists of preliminary studies in rats and rhesus monkeys along with simulations of human studies. The specific aims are to (1) develop a tracer delivery protocol and analytical tools based on exploratory studies with rats; (2) optimize the delivery protocols for monkey studies; (3) study the neuromodulatory response to an amphetamine challenge in monkeys, correlating simultaneous observations of alterations in striatal dopamine release and variations in rCBF in various brain regions; and (4) optimize the delivery protocols for human studies based on simulations.